EP0100630A2 - Analogues de la prostaglandine E1 - Google Patents

Analogues de la prostaglandine E1 Download PDF

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Publication number
EP0100630A2
EP0100630A2 EP83304242A EP83304242A EP0100630A2 EP 0100630 A2 EP0100630 A2 EP 0100630A2 EP 83304242 A EP83304242 A EP 83304242A EP 83304242 A EP83304242 A EP 83304242A EP 0100630 A2 EP0100630 A2 EP 0100630A2
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EP
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Prior art keywords
group
prostaglandin
cyclopentyl
tetrahydropyran
pge
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EP83304242A
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German (de)
English (en)
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EP0100630B1 (fr
EP0100630A3 (en
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Takashi Muryobayashi
Katsuhiro Imaki
Yoshiki Sakai
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Ono Pharmaceutical Co Ltd
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Ono Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/93—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems condensed with a ring other than six-membered
    • C07D307/935—Not further condensed cyclopenta [b] furans or hydrogenated cyclopenta [b] furans
    • C07D307/937—Not further condensed cyclopenta [b] furans or hydrogenated cyclopenta [b] furans with hydrocarbon or substituted hydrocarbon radicals directly attached in position 2, e.g. prostacyclins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
    • C07C405/0008—Analogues having the carboxyl group in the side-chains replaced by other functional groups
    • C07C405/0025—Analogues having the carboxyl group in the side-chains replaced by other functional groups containing keto groups
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
    • C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
    • C08B37/0009—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid alpha-D-Glucans, e.g. polydextrose, alternan, glycogen; (alpha-1,4)(alpha-1,6)-D-Glucans; (alpha-1,3)(alpha-1,4)-D-Glucans, e.g. isolichenan or nigeran; (alpha-1,4)-D-Glucans; (alpha-1,3)-D-Glucans, e.g. pseudonigeran; Derivatives thereof
    • C08B37/0012—Cyclodextrin [CD], e.g. cycle with 6 units (alpha), with 7 units (beta) and with 8 units (gamma), large-ring cyclodextrin or cycloamylose with 9 units or more; Derivatives thereof
    • C08B37/0015—Inclusion compounds, i.e. host-guest compounds, e.g. polyrotaxanes

Definitions

  • This invention is concerned with new prostaglandin E 1 analogues.
  • Prostaglandins are derivatives of prostanoic acid which has the following formula:
  • prostaglandin E(PGE) has the structure:
  • the dotted lines in the foregoing formulae and in other formulae throughout this specification denote, in accordance with generally accepted rules of nomenclature, that the attached grouping lies behind the general plane of the ring system, i.e. that the grouping is in a-configuration, and the thickened lines denote that the grouping lies in front of the general plane of the system, i.e. that the grouping is in 8-configuration.
  • the wavy line w in other formulae throughout this specification indicates that the grouping is in a- or ⁇ -configuration, or mixtures thereof.
  • PGE 1 prostaglandin E 1
  • Prostaglandins are generally known to possess pharmacological properties, for example they stimulate smooth muscle, have hypotensive, diuretic, bronchodilating and antilipolytic activities, and also inhibit blood platelet aggregation and gastric acid secretion, and are, accordingly, useful in the treatment of hypertension, thrombosis, asthma and gastro-intestinal ulcers, in the induction of labour and abortion in pregnant female mammals, in the prevention of arteriosclerosis, and as diuretic agents. They are fat-soluble substances obtainable in very small quantities from various tissues of animals which secrete the prostaglandins in the living body.
  • PGE's have an inhibiting effect on gastric acid secretion and may, accordingly, be used in the treatment of gastric ulcers. They also inhibit the release of free fatty acid induced by epinephrine and as a result they reduce the concentration of free fatty acid in blood, and are, accordingly, useful in the prevention of arteriosclerosis and hyperlipemia.
  • PGE l inhibits blood platelet aggregation and also removes the thrombus and prevents thrombosis.
  • PGE's have a stimulating effect on smooth muscle and increase the intestinal peristalsis; these actions indicate therapeutic utility on post-operative ileus and as purgatives.
  • PGE's may also be used as oxytocics, as abortifacients in the first and second trimesters; in the post-labour abortion of the placenta, and as oral contraceptives because they regulate the sexual cycle of female mammals.
  • PGE's have vasodilator and diuretic activities. They are useful for improvement in patients suffering from cerebral vascular disease because they increase the cerebral blood flow, and are also useful in the treatment of asthmatic conditions in patients because of their bronchodilating activity.
  • novel compounds which have the pharmacological effects of the natural prostaglandins, or which have one or more of these properties to an enhanced degree, or which have properties which are not found with the natural prostaglandins, it has been discovered that novel compounds in which the carboxy group of the 1-position of PGEl has been replaced by a hydroxymethyl group, an oxo group has been introduced into the carbon atom at the 6-position, and the n-pentyl group attached to the 15-position is replaced by certain cycloalkyl-substituted alkyl groups, or cycloalkyl groups, have a selective strong cytoprotective activity.
  • the present invention accordingly provides novel prostaglandin E 1 analogues of the general formula: (wherein R represents a single bond or a straight- or branched-chain alkylene group of from 1 to 5 carbon atoms, R 2 represents a cycloalkyl group of from 4 to 7 carbon atoms either unsubstituted or substituted by at least one straight- or branched-chain alkyl group of from 1 to 8 carbon atoms, and the double bond between C13 and C14 is trans) and cyclodextrin clathrates thereof.
  • hydroxy group attached to the C-15 carbon atom of formula (I) is in a-configuration.
  • the present invention is concerned with all compounds of general formula (I) in the 'natural' form or its enantiomeric form, or mixtures thereof, more particularly the racemic form consisting of equimolecular mixtures of natural and its enantiomeric form.
  • the compounds depicted in general formula (I) have at least four centres of chirality, these four centres of chirality being at the C-8, C-11, C-12 and C-15 carbon atoms. Still further centres of chirality may occur when R 2 is an alkylsubstituted cycloalkyl group or R is a branched-chain alkylene group.
  • R 2 is an alkylsubstituted cycloalkyl group or R is a branched-chain alkylene group.
  • the presence of chirality leads, as is well known, to the existence of isomerism.
  • the compounds of general formula (I) all have such a configuration that the side-chains attached to the ring carbon atoms in the positions identified as 8 and 12 are trans with respect to each other.
  • the grouping -R 1 -R 2 is preferably cyclobutyl, 1-propylcyclobutyl, 1-butylcyclobutyl, 1-pentylcyclobutyl, 2-propylcyclobutyl, 3-ethylcyclobutyl, 3-propylcyclobutyl, cyclopentyl, cyclopentylmethyl, 1-cyclopentylethyl, 2-cyclopentylethyl, 2-ethylcyclopentyl, 2-propylcyclopentyl, 2-butylcyclopentyl, l-methyl-3-propylcyclopentyl, 2-methyl-3-propylcyclopentyl, 3-methylcyclopentyl, 3-ethylcyclopentyl, 3-propylcyclopentyl, 3-butylcyclopentyl, 3-pentylcyclopentyl, cyclohexyl, 3-ethylcyclohexyl, 3-ethylcyclo
  • Prostaglandin E 1 analogues of the general formula (I) and cyclodextrin clathrates thereof have strong cytoprotective activity, and have very weak toxicity.
  • the prostaglandin E 1 analogues of the general formula (I) and cyclodextrin clathrates thereof may be used in the prevention and/or treatment of many kinds of diseases associated with cytodamage, as follows:
  • the compounds of the invention may therefore be used in the treatment (including preventive treatment) of diseases associated with cell damage, especially liver disease.
  • the compounds of the present invention possess relatively weak other prostaglandin-like activities such as hypotensive activity and uterine contractile activity.
  • other prostaglandin-like activities such as hypotensive activity and uterine contractile activity.
  • cytoprotective activity i.e. inhibitory activity of cytodamage is the desired pharmacological property
  • hypotensive activity, platelet aggregation inhibitory activity and uterine contractile activity which activities are known activities that prostaglandins generally possess
  • the compounds included in the present invention i.e. the compounds A, B and C, and the known compounds D, E, F and G are shown to possess cytoprotective activity.
  • compounds A, B and C of the present invention possess very weak side-effects i.e. hypotensive activity and platelet aggregation inhibiting activity, in comparison with the known compounds D, E, F and G and are therefore preferable for use in the treatment of cytodamage.
  • the compounds A, B and C are superior in their cytoprotective activity to the known compound H.
  • novel compounds of the invention which have unexpectedly been found to possess cytoprotective activity, also possess superior activity and/or selectivity in comparison with the known compounds described above (which were not hitherto known to possess cytoprotective activity).
  • the toxicities of the compounds of the present invention (expressed as the LD 50 ) have been found to be more than 10 mg/kg animal body weight by oral administration. Therefore, the compounds of the present invention may be considered to be sufficiently safe and suitable for medical use.
  • compound A i.e. 2-decarboxy-2-hydroxymethyl-6-oxo-15-(3RS-butyl-1S-cyclopentyl)-16,17, 18, 19, 20-pentanor-PGE 1
  • compound B i.e. 2-decarboxy-2-hydroxymethyl-6-oxo-15-(3RS-propyl-1S-cyclopentyl)-16,17,18,19,20-pentanor-PGE 1
  • compound C i.e. 2-decarboxy-2-hydroxymethyl-6-oxo-15-cyclopentyl-16,17,18,19,20-pentanor-PGE 1
  • compound C i.e. 2-decarboxy-2-hydroxymethyl-6-oxo-15-cyclopentyl-16,17,18,19,20-pentanor-PGE 1
  • prostaglandin E 1 analogues of the general formula (I) may be prepared by the hydrolysis, under acidic condition, of a compound of general formula: wherein R 3 represents a tetrahydropyran-2-yl, or tetrahydrofuran-2-yl group, either unsubstituted or substituted by at least one alkyl group, or a 1-ethoxyethyl group, and the other symbols are as hereinbefore defined.
  • the hydrolysis may be carried out, for example, (1) with an aqueous solution of an organic acid such as acetic acid, propionic acid, oxalic acid or p- toluenesulphonic acid, or an aqueous solution of an inorganic acid, such as hydrochloric acid or sulphuric acid, advantageously in the presence of an inert organic solvent miscible with water, e.g.
  • an organic acid such as acetic acid, propionic acid, oxalic acid or p- toluenesulphonic acid
  • an inorganic acid such as hydrochloric acid or sulphuric acid
  • a lower alkanol such as methanol or ethanol (preferably methanol), or an ether such as 1,2-dimethoxyethane, dioxane or tetrahydrofuran (preferably tetrahydrofuran), at a temperature ranging from ambient to 75 0 C (preferably at a temperature below 45°C), or (2) with an anhydrous solution of an organic acid such as p-toluenesulphonic acid or trifluoroacetic acid in a lower alkanol such as methanol or ethanol at a temperature ranging from 10 C to 45°C.
  • a lower alkanol such as methanol or ethanol (preferably methanol)
  • an ether such as 1,2-dimethoxyethane, dioxane or tetrahydrofuran (preferably tetrahydrofuran)
  • an organic acid such as p-toluenesulphonic acid or trifluoroacetic acid
  • the mild hydrolysis may be carried out with a mixture of hydrochloric acid, water and tetrahydrofuran, a mixture of hydrochloric acid, water and methanol, a mixture of acetic acid, water and tetrahydrofuran, or a mixture of p-toluenesulphonic acid and methanol.
  • Compounds of general formula (II) may be prepared by mild oxidation of a compound of general formula: (wherein the absolute configuration of the substituents on the 6-position carbon atom is S or R or an RS mixture, and the other symbols are as hereinbefore defined), which compound is in equilibrium with its tautomer of the general formula: wherein the various symbols are as hereinbefore defined.
  • the oxidation is carried out under mild, neutral conditions, for example, by reaction with (1) dimethylsulphide-N-chlorosuccinimide complex, thioanisole-N-chlorosuccinimide complex, dimethyl sulphide- chlorine complex or thioanisole-chlorine complex in a haloalkane, e.g. chloroform, methylene chloride or carbon tetrachloride, or toluene at a temperature of from -30 C to O°C [cf. J. Am. Chem. Soc., 94, 7586 (1972)], (2) chromium trioxide-pyridine complex, e.g.
  • Collins reagent in a haloalkane, e.g. chloroform, methylene chloride or carbon tetrachloride, at a temperature of from 0 0 0 C to ambient, preferably at 0 C, or (3) Jones reagent in the presence of acetone and dilute 0 sulphuric acid at a temperature of from 0 C to ambient.
  • a haloalkane e.g. chloroform, methylene chloride or carbon tetrachloride
  • the dehydrohalogenation may be carried out with a known dehydrohalogenation reagent, for example, a bicycloamine such as DBU (i.e. l,5-diazabicyclo[5.4.0]-undecene-5), DBN (i.e. l,5-diazabicyclo[4.3.0]nonene-5) or DABCO (i.e. 1,4-diazabicyclo[2.2.2]octane), or an alkali metal, e.g. sodium or potassium, lower alkoxide.
  • the reaction may be carried out at a temperature of from 40 C to 110 C, preferably at a temperature of from 40°C to 80 C.
  • the reagent used is a bicycloamine, it may be carried out with or without solvent, preferably without solvent or with toluene or benzene as solvent.
  • the reagent used is a lower alkoxide the reaction is preferably conducted using as solvent the corresponding lower alcohol.
  • the partial hydrolysis must be carried out carefully to avoid elimination of the groups R 3 , and may be carried out with an aqueous solution of an organic acid, e.g. acetic acid, propionic acid, oxalic acid or p-toluenesulphonic acid, or an aqueous solution of an inorganic acid, e.g. hydrochloric or sulphuric acid, in the presence or absence of an inert organic solvent miscible with water, e.g. an ether such as 1,2-dimethoxyethane, dioxane or tetrahydrofuran (preferably tetrahydrofuran), at a temperature of from 0 C to 75 0 C (preferably from O°C to ambient).
  • an organic acid e.g. acetic acid, propionic acid, oxalic acid or p-toluenesulphonic acid
  • an inorganic acid e.g. hydrochloric or sulphuric acid
  • the hydrolysis may be carried out with a mixture of acetic acid, water and tetrahydrofuran, a mixture of dilute hydrochloric acid and tetrahydrofuran, or dilute hydrochloric acid.
  • the progress of the hydrolysis is preferably monitored by thin layer chromatography to avoid elimination of the groups R 3 .
  • Compounds represented by the general formula (V) may be prepared by converting to a group OR 3 , the hydroxy group in the 1-position of a compound of general formula: wherein the absolute configurations of the substituents on the 5-position and the 6-position of the carbon atoms are, independently, S or R or an RS mixture and the other symbols are as hereinbefore defined.
  • This reaction is known, and may be carried out in an inert organic solvent, for example, methylene chloride, chloroform, diethyl ether, in the presence of a condensing agent, for example, p-toluenesulphonic acid, sulphuric acid, hydrochloric acid, trifluoroacetic acid, trifluoroborane etherate, phosphorus oxychloride or camphorsulphonic acid, using a 2,3-dihydropyran, 2,3-dihydrofuran or ethyl vinyl 0 ether, at a temperature of from ambient to -30 C.
  • a condensing agent for example, p-toluenesulphonic acid, sulphuric acid, hydrochloric acid, trifluoroacetic acid, trifluoroborane etherate, phosphorus oxychloride or camphorsulphonic acid, using a 2,3-dihydropyran, 2,3-dihydrofuran or
  • the compound of general formula (VI) may be prepared by reducing a compound of general formula: (wherein the absolute configurations of the substituents on the 5-position and 6-position carbon atoms are, independently, S or R or an RS mixture, and the other symbols are as hereinbefore defined) to convert the group -CHO to -CH 2 0H.
  • This reduction may be carried out, for example, in an inert organic solvent, e.g. tetrahydrofuran, methylene chloride, methanol or ethanol, using sodium borohydride, at a temperature of from -20°C to 40°C.
  • an inert organic solvent e.g. tetrahydrofuran, methylene chloride, methanol or ethanol
  • sodium borohydride at a temperature of from -20°C to 40°C.
  • it is carried out with sodium borohydride in methanol or ethanol with cooling by ice.
  • Compounds of general formula (VII) may be prepared by reducing a compound of general formula: (wherein the absolute configurations of the substituents on the 5-position and the 6-position carbon atoms are, independently, S or R or an RS mixture and R 4 represents a straight- or branched-chain alkyl group of from 1 to 4 carbon atoms, preferably a methyl group, and the other symbols are as hereinbefore defined) to convert the group -COOR 4 to -CHO.
  • This reduction may be carried out, for example, in hexane, tetrahydrofuran or toluene, using diisobutylaluminium hydride (DIBAL) and an alcohol, for example, 0 methanol or ethanol, at a temperature of from 0 C to -80 C, preferably, in toluene using DIBAL and methanol at -78 C.
  • DIBAL diisobutylaluminium hydride
  • alcohol for example, 0 methanol or ethanol
  • the compounds of the present invention of the general formula (I) may also be prepared by hydrolysis, under acidic conditions of the compounds of general formula: (wherein R 5 represents a triphenylmethyl group, or a tetrahydropyran-2-yl or tetrahydrofuran-2-ylgroup, either unsubstituted or substituted by at least one alkyl group, or a 1-ethoxyethyl group, and the other symbols are as hereinbefore defined).
  • the hydrolysis may be carried out by the method hereinbefore described for the preparation of the compounds of the general formula (I) from the compounds of the general formula (II).
  • step [a] may be conducted by reaction with lithium aluminium hydride, in an ether such as diethyl ether or tetrahydrofuran, at from room temperature to the reflux temperature of the reaction mixture.
  • ether such as diethyl ether or tetrahydrofuran
  • the step [b] may be conducted; (1) when R 5 is a triphenylmethyl group, by reaction with triphenylmethyl chloride in a tertiary amine such as pyridine, at a temperature of from 0°C to 50°C; (2) when R 5 is a tetrahydropyran-2-yl or tetrahydrofuran-2-yl group, either unsubstituted or substituted by at least one alkyl group, or a 1-ethoxyethyl group, the hydroxymethyl group attached to the 1 position of the compounds of the general formula (XI) is suitably converted to a group -CH 2 0R 5 in which R 5 is other than triphenylmethyl by reaction in an inert organic solvent such as methylene chloride, chloroform or diethyl ether, in the presence of a condensing agent such as p-toluenesulphonic acid, sulphuric acid or hydrochloric acid, with a 2,3-di
  • Step [c] may be conducted; (1) when X is aniodine atom, by reaction with iodine, in an inert organic solvent such as methylene chloride or chloroform, in the presence of a bicarbonate of an alkali metal such as sodium or potassium at a temperature of from -20°C to 40°C: (2) when X is a bromine atom, by reaction with N-bromosuccinimide (NBS) in an aprotic solvent such as methylene chloride or tetrahydropyran, at a temperature of from room temperature to 0°C.
  • NBS N-bromosuccinimide
  • the step [d] may be carried out by the method hereinbefore described for preparing the compounds of the general formula (IV) from the compounds of the general formula (V).
  • step [el may be carried out by the method hereinbefore described for preparing the compounds of the general formula (II) from the compounds of the general formula (IV).
  • steps [a] to [e] may be used without purification, in subsequent steps.
  • the compounds of the general formula (X) may be obtained by the methods described in British Patent specification No.1545213.
  • Cyclodextrin clathrates of the prostaglandin E 1 analogues of the general formula (I) may be prepared using ⁇ -, ⁇ - or y-cyclodextrin or mixtures thereof, by the process described in the specifications of United States Patent Nos. 3,816,393 and 4,054,736.
  • cyclodextrin clathrates are preferred for pharmaceutical use.
  • Preferred compounds included in the compounds of the general formula (I) are, for example:
  • the reaction mixture was diluted with ethyl acetate, and the diluted solution was washed successively with dilute hydrochloric acid, an aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulphate and concentrated under reduced pressure.
  • the residue was purified by column chromatography on silica gel using a mixture of cyclohexane and ethyl acetate (2:1) as eluent to give 0.552 g of the title compound in a 72.5% yield, having the following physical characteristics:
  • the extract was washed successively with water, an aqueous solution of sodium bicarbonate, and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulphate and concentrated under reduced pressure.
  • the residue was purified by column chromatography on silica gel using a mixture of cyclohexane and ethyl acetate (5:1 ⁇ 4:1) as eluent to give 0.354 g of the title compound, in a 74.2% yield having the following physical characteristics:
  • compositions which comprise at least one prostaglandin analogue of general formula (I) or cyclodextrin clathrate thereof, together with a pharmaceutical carrier or coating.
  • the compounds of the present invention will normally be administered systemically or partially; usually by oral or parenteral (.e.g. intravenous, subcutaneous or intramuscular) administration.
  • Solid compositions for oral administration include compressed tablets, pills, dispersible powders, and granules.
  • one or more of the active compound(s) is, or are, admixed with at least one inert diluent such as lactose, mannitol, glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone or magnesium metasilicate aluminate.
  • the compositions may also comprise, as is normal practice, additional substances other than inert diluents, e.g. lubricating agents such as magnesium stearate, and disintegrating agents, such as cellulose calcium gluconate.
  • the tablets or pills may, if desired,be made into enteric film-coated or gastric film-coated tablets or pills, such as sugar-coated, gelatin-coated, hydroxypropylcellulose-coated or hydroxypropylmethylcellulose phthalate-coated tablets or pills; two or more layers may be used.
  • enteric film-coated or gastric film-coated tablets or pills such as sugar-coated, gelatin-coated, hydroxypropylcellulose-coated or hydroxypropylmethylcellulose phthalate-coated tablets or pills; two or more layers may be used.
  • compositions for oral administration also include capsules of absorble material such as gelatin, containing one or more of the active substances with or without the addition of diluents or excipients.
  • Liquid compositions for oral administration include pharmaceutically-acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents commonly used in the art such as distilled water or ethanol. Besides inert diluents such compositions may also comprise adjuvants such as wetting and suspending agents, and sweetening, flavouring, perfuming and preserving agents.
  • compositions for oral administration include spray compositions which may be prepared by known methods and which comprise at least one compound of the present invention.
  • Preparations according to the invention for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions or emulsions.
  • aqueous solvents or suspending media are distilled water for injection and physiological salt solution.
  • non-aqueous solvents or suspending media are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, and Polysorbate 80 (registered Trade Mark).
  • These compositions may also include adjuvants such as preserving, wetting, emulsifying and dispersing agents. They may be sterilized, for example, by filtration through a bacteria-retaining filter, by incorporation of sterilizing agents in the compositions or by irradiation. They may also be manufactured in the form of sterile solids compositions which can be dissolved in sterile water or some other sterile injectable medium immediately before use.
  • compositions include, for parenteral administration, liquids for external use, and endermic liniments such as ointments; suppositories for rectal administration; and pessaries for vaginal administration.
  • endermic liniments such as ointments
  • suppositories for rectal administration
  • pessaries for vaginal administration.
  • Such compositions are prepared by known methods.
  • compositions of the invention may be varied, it being necessary that it should constitute a proportion such that a suitable dosage for the therapeutic effect desired shall be obtained. Obviously several unit dosage forms may be administered at about the same time.
  • preparations should normally contain at least 0.025% by weight of active substance when required for administration by injection; for oral administration the preparations will normally contain at least 0.1% by weight of active substance.
  • the dose to be administered is determined depending upon, for example, age, symptoms, the desired therapeutic effects, the route of administration, and the duration of the treatment.
  • the doses per person are generally between 0.1 and 100 ⁇ g, preferably between 1 and 50 ⁇ g by oral administration, and between 0.01 and 50 ⁇ g, preferably between 0.1 and 20 ⁇ g by parenteral administration in the treatment of cyto-damage, and can be administered up to several times per day.
  • the doses to be used depend on various conditions. Therefore, there may be cases in which doses greater than the ranges specified above, or lower than the ranges specified above, may be used.
  • Tablets, capsules, soft capsules and solutions for injection were prepared using the compounds of Example l(a) and l(b) as an active ingredient, in the same manner as described in Example 2, 3, 4 and 5.
  • Rats Male Wistar rats weighing 180 - 220 g were used. Rats were dosed intraperitoneally with CC1 4 dissolved in olive oil (5%, w/v) at a volume of 500 ⁇ l/kg after 18 hr starvation. The compound under test was administered orally (p.o.) or subcutaneously (s.c.) 6 and 12 hr after CC1 4 injection in rats and blood was collected after 24 hr. Plasma glutamic oxaloacetic transaminase (GOT) and glutamic pyruvic transaminase (GPT) activities were determined by ultraviolet absorbance methods (optimised method based on the recommendations of the Deutsche Deutschen fur Klinische Chemie). The effects of the compounds tested were assessed by the inhibition rate in comparison with controls. Inhibition rate was calculated by the following formula.
  • Inhibition (%) (1 - treated value ) x 100 control value
  • ⁇ -naphthylisothiocyanate dissolved in olive oil (1.5% w/v) was given orally to them at 30 mg/kg body weight.
  • the compound under test was administered orally 30 min before and 6 and 12 hr after administration of ANIT and blood was collected after 24 hr.
  • Plasma GOT, GPT and bilirubin activities were determined and the results calculated by the formula shown in Experiment 1 by comparison with controls.
  • mice Male Wistar rats weighing 180 - 220 g were used. After the rats had fasted for 18 hr, 250 mg/kg galactosamine hydrochloride was administered to them intraperitoneally three times at 4 hr intervals. The compound under test was administered orally 6, 12, 18, 24, 30, 36, 42 and 48 hr after the dose of D(+)-galactosamine hydrchloride and blood was collected after 36, 48 and 54 hr. Plasma GOT and GPT activities were determined in the manner described in Experiment 1 and the effects were shown by the inhibition rate compared with controls (calculation by the formula shown in Experiment 1). Plasma bilirubin activities were also determined.

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EP83304242A 1982-07-22 1983-07-21 Analogues de la prostaglandine E1 Expired EP0100630B1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AT83304242T ATE18904T1 (de) 1982-07-22 1983-07-21 Prostaglandin-e1-analogen.

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP57126665A JPS5920267A (ja) 1982-07-22 1982-07-22 プロスタグランジンｅ↓１類似化合物
JP126665/82 1982-07-22

Publications (3)

Publication Number Publication Date
EP0100630A2 true EP0100630A2 (fr) 1984-02-15
EP0100630A3 EP0100630A3 (en) 1984-08-08
EP0100630B1 EP0100630B1 (fr) 1986-04-02

Family

ID=14940835

Family Applications (1)

Application Number Title Priority Date Filing Date
EP83304242A Expired EP0100630B1 (fr) 1982-07-22 1983-07-21 Analogues de la prostaglandine E1

Country Status (5)

Country Link
US (1) US4473587A (fr)
EP (1) EP0100630B1 (fr)
JP (1) JPS5920267A (fr)
AT (1) ATE18904T1 (fr)
DE (1) DE3362787D1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5591446A (en) * 1989-04-04 1997-01-07 Beiersdorf, A.G. Methods and agents for the prophylaxis of atopy

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2805870B2 (ja) * 1989-07-31 1998-09-30 ソニー株式会社 周波数発電機
JP4648340B2 (ja) * 2006-02-07 2011-03-09 株式会社アールテック・ウエノ １５−ケトプロスタグランジンｅ誘導体の製造法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2376134A1 (fr) * 1976-12-30 1978-07-28 Upjohn Co Derives de 6-oxo-prostaglandines, leur procede de preparation et medicaments en contenant
EP0068871A2 (fr) * 1981-06-29 1983-01-05 Ono Pharmaceutical Co., Ltd. Analogues de prostaglandin

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2376134A1 (fr) * 1976-12-30 1978-07-28 Upjohn Co Derives de 6-oxo-prostaglandines, leur procede de preparation et medicaments en contenant
EP0068871A2 (fr) * 1981-06-29 1983-01-05 Ono Pharmaceutical Co., Ltd. Analogues de prostaglandin

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5591446A (en) * 1989-04-04 1997-01-07 Beiersdorf, A.G. Methods and agents for the prophylaxis of atopy

Also Published As

Publication number Publication date
JPH024590B2 (fr) 1990-01-29
DE3362787D1 (de) 1986-05-07
EP0100630B1 (fr) 1986-04-02
JPS5920267A (ja) 1984-02-01
EP0100630A3 (en) 1984-08-08
US4473587A (en) 1984-09-25
ATE18904T1 (de) 1986-04-15

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